Filthy Places for Antibiotics

Alexander Fleming’s discovery of penicillin is one of the great tales of a medical breakthrough drawn from nature. While growing cultures of staphylococci, he noticed that one dish was contaminated with a mold that had killed all the bacteria adjacent to it. The mold, Fleming learned, had a natural capacity to clear away bacteria by lysing their cell walls. And so the age of antibiotics began.

Testing antibiotics (Credit: CDC/Don Stalons)

Bacteria continue to acquire resistance to antibiotics at a terrifying rate, and pharmaceutical makers have far too few possibilities for effectiveness new replacements in development. So, up to a point, it’s good news this week that at least a couple more novel candidates have turned up—in some of the least sanitary, least likely places one might imagine. I’ll keep my enthusiasm under wraps for reasons I’ll discuss presently, but first: where are these new leads for antibiotics coming from?

In the brains of cockroaches and locusts

At the Society for General Microbiology meeting at the University of Nottingham, Simon Lee reported that his group at the university’s School of Veterinary Medicine and Science had isolated proteins with powerful antibiotic properties from the brains of insects. As the BBC reports:

The researchers discovered nine different chemicals in the brains of locusts and cockroaches, which all had anti microbial properties strong enough to kill 90% of MRSA (Methicillin-resistant Staphylococcus aureus) while not harming human cells.

<…>

“A kill rate of 90% is very very high, and I diluted the substance down so there was only a minute amount there. Conventional antibiotics reduce the number of the bacteria and let your immune system cope with the rest. So to get something with such a high kill rate that is so potent at such a low dose is very promising,” [Lee] told BBC News.

American cockroach (Credit: Colin Ybarra)

The rationale for the researchers choosing to look inside insect pests for antibiotics seems to be that because cockroaches can thrive in filthy environments, they must have ways to protect themselves against lethal infections. The Nottingham researchers are certainly not the first to have that insight. Insects do have astonishingly sophisticated innate immune systems that are built around antimicrobial compounds; they lack an adaptive immune system, like ours, that manufacture antibodies and lymphocytes against specific invaders.

But why would these antibiotic proteins only be found in the cockroaches’ nervous systems and not their other tissues, which are of course equally subject to infection? Lee’s answer:

“They must have some sort of defense against micro organisms. We think their nervous system needs to be continuously protected because if the nervous system goes down the insect dies. But they can suffer damage to their peripheral structures without dying,” he told BBC News.

Well… maybe. Given that cockroaches can technically survive without heads (and brains) for weeks and yet removing other parts of their body can significantly impair their learned behaviors (according to Scientific American), I’m not convinced it’s open and shut that they need their nervous systems uniquely more than other tissues. Still, that’s almost beside the point: if these compounds hold real promise as antibiotic drugs, we’ll take them.

In cannibalistic bacteria

Bacillus subtilis (Credit: Allon Weiner)

Wei-Ting Liu, Yu-Liang Yang, Yuquan Xu of the University of California at San Diego and their collaborators have reported in PNAS that they have identified antibiotic peptides involved in a cannibalistic strategy that the bacterium Bacillus subtilis uses to survive under difficult conditions.

B. subtilis is a soil bacterium widely cultured in laboratories and has with few pathogenic effects in humans; about the worst that it usually does is make the consistency of contaminated bread dough stringy. Like many bacteria, its cells can survive lean times when nutrients are in short supply by converting themselves into hardy inert spores. But this conversion process itself takes extra nutrients. Some ghoulish B. subtilis cells escape this Catch-22 dilemma by releasing molecules that induce their own neighboring siblings to commit suicide, then eating their remains.

Normally, Bacillus subtilis uses SDP on its neighbors, which tend to be other Bacillus subtilis. But there’s no reason to think that these chemicals would necessarily be specific to one type of bacteria, so the authors tried it on a number of others. It turned out to kill a number of pathogenic bacteria, including methicillin-resistant S. aureus, better known as MRSA, the multidrug-resistant bacteria. In fact, it was effective down to concentrations similar to vancomycin, a drug known to be effective against MRSA.

Although developing any of these into a drug would be a long process, the authors suggest the general approach—using this technique to snoop on the chemical warfare that occurs at the microbial level—might be generally effective at identifying other naturally occurring antibiotics. Given the rise of drug resistance and the small number of drugs in development, any potential new leads can only be seen as a good thing.

Here, here.

So what are my reservations?

Why can I only muster half-hearted cheers for these announcements? In the case of the B. subtilis discovery, my disappointment is just that even if the SDP does continue to look promising—and its effects do need to be replicated in other labs—it is almost certainly a decade or more away from clinical trials, which will be far too late for many victims of MRSA and other resistant bacteria. And of course, very few new drug possibilities turn out to work as well as hoped. But virtually any novel antibiotic candidate faces those obstacles—which is why the rising resistance problem is so dire—so I can’t point to anything in this work that is especially questionable.

My leeriness of the cockroach antimicrobials has a more specific basis. First, let’s recognize the tentativeness of the report. This news was presented at a professional meeting, which is not the same as publishing it in a peer-reviewed journal. I point out the publication status with no prejudice against Lee and his colleagues, who no doubt fully intend to present it for publication in the future, but we should bear in mind that the work hasn’t yet had the benefit of being fully vetted or replicated. (Note that this write-up at Physorg, by the way, is apparently based entirely on a press release from the University of Nottingham.) No informed, independent commentary on the studies seems to be available yet. So reserve judgment.

Also, although the idea of novel antibiotics derived from insects that live in germ-ridden circumstances sounds appealingly sensible, I can’t help but be reminded of this story from a couple of weeks ago about novel antibiotic compounds found in frog skin. Which also makes perfect sense, doesn’t it, because frogs, too, need special resources to help them survive in filthy, microbe-rich water.

The stories behind certain drug candidate molecules are so fun and compelling and sensible that you can’t help but think they will work out. And sometimes they do. But more often, they don’t, no matter how great the stories are.

10 Responses to Filthy Places for Antibiotics

The fact is, it’s not actually terribly hard to find things that kill bacteria; what’s difficult is to find things that kill bacteria, but that also don’t depolarise human cell membranes too. The vast majority of agents found tend to have some effect on membranes, and they’re largely non-specific. This is not to say that these Indiana Jones -like hunts for the ultimate antibiotic in nature aren’t worthwhile (remember ‘crocodillin’ – from crocodile blood – from 2005?), but they are prematurely hyped.

As regards anti-microbial peptides. In theory, they are a nice idea. In practise, I’ve seen evidence that they breed resistance far more readily than is often touted, and I never really liked the idea of subjecting chemical moieties that are an integral part of our own innate immune system to the vagaries of potential resistance development.

Eli Lilly & Co. found the source of vancomycin in mud from the jungle floor of Borneo, and daptomycin in dirt from the slopes of Mt. Ararat. Kind of a nice parallelism that, as bacteria become more resistant, it is necessary to go to dirtier places in response. (Though, stepping back, are cockroaches actually “dirtier,” that is, carrying more pathogenic organisms? Or is the issue that, out of our innate or learned emotional reaction to them, we classify them as “dirtier” when they are not in fact?)

Good question. I’ve heard—though I can’t vouch for it—that notwithstanding our revulsion at roaches and their fondness for what we consider nasty places, roaches actually tend to be rather fastidious in their personal hygiene. They clean and groom themselves quite a bit, for example. Of course, lots of insects groom themselves, and I don’t know whether roaches do so more than most.

Interesting fields of research, sure. I suppose there’s no harm in thinking outside the box of available compounds, besides the money and time spent researching them. I have to agree with with your assesment though; until it’s viable for use in vivo, it’s just a great punchline.

Another interesting field of antibiotic research playing out as we speak is phage therapie, although this falls outside the field of compound reseach. Personally I’ve never considered viri as dirty, but I can already imagine the general trepedation of willingly having youself injected with them to combat a bacterial infection.

I agree, the viral therapies that are being contemplated and studied are extremely interesting, not least because of the historical collapse of that area of research decades ago. It does seem like these ought to be useful at some point. But you’re right, getting people to accept the idea of exposing themselves to viruses might be tricky (though it’s done with some vaccines now). My cautionary note still applies in the end: we need to be careful that our desire for certain approaches to work doesn’t blind us to the fact that much of the time, even seemingly good ideas fail.

The Gleaming Retort — Meet the Author

John Rennie served as editor in chief of Scientific American between 1994 and 2009. Based in New York, he continues to work as a science writer and editor, and as an adjunct instructor in New York University's Science, Health and Environmental Reporting Program. John can be found on Twitter as @tvjrennie.

Commenting Policy

Here at the PLoS Blogs, we try to keep things civil and neat. Frank disagreements and dissenting opinions are welcome, but please avoid obscenity, libel and other rude behaviors. Decisions of the management are arbitrary and final. Remember, I’m an editor: making writers’ words disappear is what I do.